Antimicrobial peptides are key effector molecules of the innate immune system and integral components of the first line of defence against microbial infections of all eukaryotic organisms. A number of prokaryotic organisms also utilise antimicrobial peptides as means to compete against challenge from other microorganisms. Many antimicrobial peptides are characterised by cationic properties that facilitate interactions with the negatively charged phospholipids of the microbial membrane which then lead to microbial lysis and death following subsequent membrane permeabilisation. For example, it has been shown that antimicrobial peptide molecules can aggregate and form voltage dependent channels in the lipid bilayer resulting in the permeabilization of both the inner and outer membrane of the microorganism (Lehrer, R. I., J. Clin. Investigation, 84:553 (1989)). The amphiphilic nature of these molecules may also facilitate the insertion of the hydrophobic residue into the lipid bilayer by electrostatic attraction while the polar residues project into and above the membrane.
Drug resistant microorganisms, especially bacteria, are becoming increasingly problematic as infection rates continue to rise and effective methods of control become more and more limited. Prolific use of antibiotics over the last 50 or so years together with the indiscriminate prescribing of antibiotics and patient non-compliance with treatment regimes, has selected for microorganisms that have developed or acquired ways of overcoming the effects of antibiotics. The transmission and control of drug-resistant organisms is becoming one of the most significant problems within healthcare.
Of particular note are strains of Staphylococcus spp. that have developed or obtained varying levels of resistance to antibiotics such as methicillin (meticillin). These strains are commonly known as methicillin resistant Staphylococcus aureus (MRSA). In addition, coagulase-negative Staphylococci, such as Staphylococcus epidermidis, have also emerged as important nosocomial pathogens. Approximately 80% of S. epidermidis isolates from device-associated infections are methicillin resistant (MRSE) as well as being multi-resistant. The treatment options for infections contributed to or caused by methicillin resistant bacteria such as MRSA and MRSE, are now limited and there is an urgent need to discover new therapies which inhibit or kill such organisms.
Pseudomonas aeruginosa is an opportunistic pathogen that causes urinary tract infections, respiratory system infections, dermatitis, soft tissue infections, bacteraemia and a variety of systemic infections, particularly in victims of severe burns and in cancer and AIDS patients who are immunosuppressed. Respiratory infections caused by Pseudomonas aeruginosa occur almost exclusively in individuals with a compromised lower respiratory tract or a compromised systemic defence mechanism. Primary pneumonia occurs in patients with chronic lung disease and congestive heart failure. Bacteraemic pneumonia commonly occurs in neutropenic cancer patients undergoing chemotherapy. Lower respiratory tract colonisation of cystic fibrosis patients by mucoid strains of Pseudomonas aeruginosa is common and difficult to treat. There is a need to develop an effective means of treating Pseudomonas aeruginosa infections.
Since microbial pathogens do not readily acquire resistance to cationic peptides, despite evolutionary pressure from millions of years of co-existence, there has been much in the way of commercial interest and effort in developing cationic peptides as potential antimicrobial therapeutics. For example, in our co-pending application, WO 2006/018652, we describe the identification of peptides that can be used to treat microbial infections including certain bacterial infections.
There is still a pressing need for further antimicrobial actives that can be used in the treatment of bacterial infections such as those caused by Staphylococcal and Pseudomonad strains.